Phase-change nanoparticle

ABSTRACT

Apparatus and methods are described for use with a subject suffering from cancer. A nanoparticle ( 22 ) includes an inner core ( 30 ) that comprises a phase-change material that is configured to absorb latent heat of fusion by undergoing a phase change. An outer layer ( 32 ) disposed around the inner core includes a plurality of nano-spheres ( 34 ) of at least one metal, and a plurality of molecules ( 38 ) of a substance that binds preferentially with cancerous cells relative to non-cancerous cells. The nanoparticle has a volume of at least 65,000 nm 3  and is elongatable into an ellipsoid, such that, when the nanoparticle is maximally elongated, each of the semi-axes defined by the ellipsoid is greater than 5 nm, and at least two of the semi axes of the ellipsoid are less than 30 nm. Other applications are also described.

CROSS REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of PCT Application no.PCT/IL2015/051146 to Hof, entitled “Phase-change nanoparticle,” filedNov. 25, 2015 (published as WO 16/084082), which claims priority fromU.S. Provisional Application 62/083,978 to Hof, entitled “Phase-changenanoparticle,” filed Nov. 25, 2014.

The present application is related to U.S. Ser. No. 13/392,037 (issuedas U.S. Pat. No. 9,572,695) to Hof, which is the US National Phase ofInternational Patent Application PCT/IL2010/000683 (published as WO11/024,159) to Hof, entitled “Phase-change and shape-change materials,filed Aug. 22, 2010, which claims priority from:

U.S. Provisional Patent Application 61/275,068 to Hof, entitled “Phasechange implant,” filed Aug. 24, 2009;

U.S. Provisional Patent Application 61/275,071 to Hof, entitled “Shapeand function change of implanted element,” filed Aug. 24, 2009;

U.S. Provisional Patent Application 61/275,089 to Hof, entitled “Phasechange materials for treating cancer,” filed Aug. 24, 2009.

All of the above-referenced applications are incorporated herein byreference.

FIELD OF EMBODIMENTS OF THE INVENTION

Some applications of the present invention generally relate to implantedmedical apparatus. Specifically, some applications of the presentinvention relate to the use of phase-change materials.

BACKGROUND

Hyperthermia is a method of treating cancer, in which heat is applied totissue of the cancer patient, in order to kill cancer cells within thetissue. Hyperthermia is typically used to treat cancer patients incombination with other therapies, such as radiotherapy and chemotherapy.

The Warburg effect describes the observation that most cancer cellspredominantly produce energy by glycolysis followed by lactic acidfermentation, rather than by oxidation of pyruvate like most healthycells. The Warburg effect results in cancer cells consuming more than 20times the quantity of glucose to produce energy than do healthy cells,ceteris paribus.

When a solid material is heated until its melting point, the materialundergoes a phase-change to its liquid state. During the phase-change,the material accumulates a certain amount of heat, which is called thelatent heat of fusion, or the enthalpy change of fusion. The temperatureof the material stays relatively constant when the phase change occurs.

SUMMARY OF EMBODIMENTS

In accordance with some applications of the present invention, aplurality of nanoparticles are administered to a subject who issuffering from cancer. The nanoparticles typically have the followingcharacteristics:

(1) The nanoparticles preferentially bind to cancerous cells relative tohealthy cells.

(2) The nanoparticles preferentially absorb energy transmitted towardthe subject's body relative to absorption of the energy by tissue of thesubject.

(3) The nanoparticles prevent healthy tissue surrounding the cancerouscells from being heated to a temperature that is greater than a giventemperature.

(4) The nanoparticles are at least partially self-adjusting in shape,the nanoparticles being configured to be elongatable to an ellipsoidshape such as to pass through a gap in an anatomical barrier that has asize that is greater than a minimum threshold size, for example, inresponse to osmotic and/or hydrostatic pressure being exerted on thenanoparticles.

It is noted that typically, the nanoparticles will not become elongatedto a precise geometric ellipsoid shape, but will assume a generallyellipsoidal shape when maximally elongated.

A heating device is typically used in conjunction with theadministration of the nanoparticles to the subject. The heating deviceacts as an energy transmission unit that transmits energy toward thesubject's body, causing at least some of the cancerous cells to becomeheated, such that the heated cells become injured, or ruptured, leadingto cell death.

There is therefore provided, in accordance with some applications of thepresent invention, apparatus for use with a subject suffering fromcancer, a body of the subject containing cancerous cells andnon-cancerous cells, and for use with a heating device configured toheat at least a portion of the subject's body, the apparatus including:

a nanoparticle including:

-   -   an inner core that includes a phase-change material that is        configured to absorb latent heat of fusion by undergoing a phase        change selected from the group consisting of: solid to liquid,        and gel to liquid, the phase-change occurring at a phase-change        temperature of between 42° C. and 80° C.;    -   an outer layer disposed around the inner core, the outer layer        including:        -   a plurality of nano-spheres of at least one metal; and        -   a plurality of molecules of a substance that binds            preferentially with cancerous cells relative to            non-cancerous cells,

the nanoparticle having a volume of at least 65,000 nm³,

the nanoparticle being elongatable into an ellipsoid, such that when thenanoparticle is maximally elongated:

-   -   each of the semi-axes defined by the ellipsoid is greater than 5        nm, and    -   at least two of the semi axes of the ellipsoid are less than 30        nm.

For some applications, the phase-change material is configured toundergo the selected phase change at a phase-change temperature ofbetween 42° C. and 50° C.

For some applications, the phase-change material is configured toundergo the selected phase change at a phase-change temperature ofbetween 50° C. and 60° C.

For some applications, the phase-change material is configured toundergo the selected phase change at a phase-change temperature ofbetween 60° C. and 80° C.

For some applications, the nanoparticle is configured to becomeelongated in response to hydrostatic pressure within the subject's body.

For some applications, the nanoparticle is configured to becomeelongated in response to osmotic pressure within the subject's body.

For some applications, the nanoparticle is configured to be blocked frompassing through a blood brain barrier of the subject, by beingelongatable into an ellipsoid, such that even when the nanoparticle ismaximally elongated, each of the semi-axes defined by the ellipsoid isgreater than 5 nm.

For some applications, the nanoparticle is configured to be able to passthrough a liver of the subject, by being elongatable into an ellipsoid,such that when the nanoparticle is maximally elongated at least two ofthe semi axes of the ellipsoid are less than 30 nm.

For some applications, the nanoparticle is configured to be able to passthrough glands of the subject, by being elongatable into an ellipsoid,such that when the nanoparticle is maximally elongated at least two ofthe semi axes of the ellipsoid are less than 30 nm.

For some applications, the nanoparticle is configured to be able to passthrough a mononuclear phagocyte system of the subject, by beingelongatable into an ellipsoid, such that when the nanoparticle ismaximally elongated at least two of the semi axes of the ellipsoid areless than 30 nm.

For some applications, the nanoparticle is configured to be able to passthrough a spleen of the subject, by being elongatable into an ellipsoid,such that when the nanoparticle is maximally elongated at least two ofthe semi axes of the ellipsoid are less than 30 nm.

For some applications, the phase-change material is configured toprevent the nanoparticle from being heated to a temperature that isgreater than the phase change temperature, by absorbing latent heat offusion.

For some applications, the nanoparticle is elongatable into anellipsoid, such that when the nanoparticle is maximally elongated eachof the semi-axes defined by the ellipsoid is greater than 10 nm.

For some applications, the nanoparticle is elongatable into anellipsoid, such that when the nanoparticle is maximally elongated atleast two of the semi axes of the ellipsoid are less than 25 nm.

For some applications, the nano-spheres of the at least one metal areconfigured to cause the nanoparticle to preferentially absorb energyfrom the heating device relative to tissue of the subject.

For some applications, the nano-spheres of the at least one metalinclude gold nano-spheres.

For some applications, the plurality of molecules of the substance thatbinds preferentially with cancerous cells relative to non-cancerouscells include a plurality of glucose molecules.

For some applications, the plurality of molecules of the substance thatbinds preferentially with cancerous cells relative to non-cancerouscells include a plurality of molecules of a glucose derivative.

For some applications, the plurality of molecules of the substance thatbinds preferentially with cancerous cells relative to non-cancerouscells include a plurality of molecules of a glucose analog.

For some applications, the plurality of molecules of the substance thatbinds preferentially with cancerous cells relative to non-cancerouscells include a plurality of molecules of an antibody.

For some applications, the nanoparticle further includes a plurality ofpolymer chains disposed between the inner core and the outer layer, theouter layer being bound to the inner core via the polymer chains.

For some applications, the polymer chains include chains of apolyetheramine.

For some applications, the nanoparticle further includes a plurality ofpolymer chains disposed around the outer layer.

For some applications, the polymer chains include chains of apolyetheramine.

For some applications, the polymer chains are configured to at leastpartially mask at least the outer layer from phagocytic cells of amononuclear phagocyte system of the subject.

For some applications, the nanoparticles are configured to be used withan inductive radiofrequency heating device, and the nano-spheres areconfigured to be heated by the inductive radiofrequency heating device.

For some applications, the nanoparticles are configured to be used withan inductive radiofrequency heating device that transmits RF energy at agiven frequency, and the nano-spheres have a resonant frequency thatmatches the given frequency.

For some applications, each of the nano-spheres has a diameter that isbetween 1 nm and 10 nm.

For some applications, each of the nano-spheres has a diameter that isbetween 3 nm and 7 nm.

For some applications, each of the nano-spheres is separated from allothers of the nano-spheres of the outer layer by a minimum separation ofbetween 0.3 nm and 2 nm.

For some applications, each of the nano-spheres is separated from allothers of the nano-spheres of the outer layer by a minimum separation ofbetween 0.5 nm and 1.5 nm.

For some applications, the inner core has a volume of 50,000-270,000nm³.

For some applications, the inner core has a volume of 85,000-145,000nm³.

For some applications, the nanoparticle has a volume of 110,000-700,000nm³. For some applications, the nanoparticle has a volume of180,000-525,000 nm³.

For some applications, the phase-change material includes an organicphase-change material.

For some applications, the phase-change material includes paraffin.

There is further provided, in accordance with some applications of thepresent invention, a method for use with a subject suffering fromcancer, a body of the subject containing cancerous cells andnon-cancerous cells, the method including:

providing a plurality of nanoparticles, each of the nanoparticlesincluding:

-   -   an inner core that includes a phase-change material that is        configured to absorb latent heat of fusion, by undergoing a        phase change selected from the group consisting of: solid to        liquid, and gel to liquid, the phase-change occurring at a        phase-change temperature of between 42° C. and 80° C., an outer        layer disposed around the inner core, the outer layer including:        -   a plurality of nano-spheres of at least one metal, and        -   a plurality of molecules of a substance that binds            preferentially with cancerous cells relative to            non-cancerous cells,    -   the nanoparticle having a volume of at least 65,000 nm3,    -   each of the nanoparticles being elongatable into an ellipsoid,        such that when the nanoparticle is maximally elongated:        -   each of the semi-axes defined by the ellipsoid is greater            than 5 nm, and        -   at least two of the semi axes of the ellipsoid are less than            30 nm; and administering the plurality of nanoparticles to            the subject.

For some applications, the method further includes, subsequent toadministering the plurality of nanoparticles to the subject, heating atleast a portion of the subject's body to the phase-change temperature ofthe phase-change material, using a heating device.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the nanoparticles being configured to become elongated inresponse to hydrostatic pressure within the subject's body.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the nanoparticles being configured to become elongated inresponse to osmotic pressure within the subject's body.

For some applications, administering the plurality of nanoparticles tothe subject includes preventing the nanoparticles from passing through ablood brain barrier of the subject, due to each of the nanoparticlesbeing elongatable into an ellipsoid, such that even when thenanoparticle is maximally elongated, each of the semi-axes defined bythe ellipsoid is greater than 5 nm.

For some applications, administering the plurality of nanoparticles tothe subject includes facilitating the nanoparticles passing throughglands of the subject, due to each of the nanoparticles beingelongatable into an ellipsoid, such that when the nanoparticle ismaximally elongated at least two of the semi axes of the ellipsoid areless than 30 nm.

For some applications, administering the plurality of nanoparticles tothe subject includes facilitating the nanoparticles passing through amononuclear phagocyte system of the subject, due to each of thenanoparticles being elongatable into an ellipsoid, such that when thenanoparticle is maximally elongated at least two of the semi axes of theellipsoid are less than 30 nm.

For some applications, administering the plurality of nanoparticles tothe subject includes facilitating the nanoparticles passing through aliver of the subject, due to each of the nanoparticles being elongatableinto an ellipsoid, such that when the nanoparticle is maximallyelongated at least two of the semi axes of the ellipsoid are less than30 nm.

For some applications, administering the plurality of nanoparticles tothe subject includes facilitating the nanoparticles passing through aspleen of the subject, due to each of the nanoparticles beingelongatable into an ellipsoid, such that when the nanoparticle ismaximally elongated at least two of the semi axes of the ellipsoid areless than 30 nm.

For some applications, administering the plurality of nanoparticles tothe subject includes administering a plurality of nanoparticles to thesubject, each of the nanoparticles being elongatable into an ellipsoid,such that when the nanoparticle is maximally elongated at least two ofthe semi axes of the ellipsoid are less than 25 nm.

For some applications, administering the plurality of nanoparticles tothe subject includes administering a plurality of nanoparticles to thesubject, each of the nanoparticles being elongatable into an ellipsoid,such that when the nanoparticle is maximally elongated each of thesemi-axes defined by the ellipsoid is greater than 10 nm.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the nano-spheres of the metal of the outer layer of thenanoparticles including gold nano-spheres.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the substance that binds preferentially with cancerous cellsrelative to non-cancerous cells including glucose.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the substance that binds preferentially with cancerous cellsrelative to non-cancerous cells including a glucose derivative.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the substance that binds preferentially with cancerous cellsrelative to non-cancerous cells including a glucose analog.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the substance that binds preferentially with cancerous cellsrelative to non-cancerous cells including an antibody.

For some applications, administering the plurality of nanoparticles tothe subject includes preventing the nanoparticles from being heated to atemperature that is greater than the phase change temperature, inresponse to the heating of the portion of the subject's body, due to thephase-change material of the inner core of the nanoparticles absorbinglatent heat of fusion.

For some applications, administering the plurality of nanoparticles tothe subject includes causing the nanoparticles to preferentially absorbenergy from the heating device relative to tissue of the subject, due tothe nano-spheres of the metal absorbing energy from the heating device.

For some applications:

administering the plurality of nanoparticles to the subject includesadministering the plurality of nanoparticles to the subject, thephase-change material of each of the nanoparticles having a phase-changetemperature of between 42° C. and 50° C.; and

heating at least the portion of the subject's body to the phase-changetemperature of the phase-change material includes heating at least theportion of the subject's body to a temperature of between 42° C. and 50°C.

For some applications:

administering the plurality of nanoparticles to the subject includesadministering the plurality of nanoparticles to the subject, thephase-change material of each of the nanoparticles having a phase-changetemperature of between 50° C. and 60° C.; and

heating at least the portion of the subject's body to the phase-changetemperature of the phase-change material includes heating at least theportion of the subject's body to a temperature of between 50° C. and 60°C.

For some applications:

administering the plurality of nanoparticles to the subject includesadministering the plurality of nanoparticles to the subject, thephase-change material of each of the nanoparticles having a phase-changetemperature of between 60° C. and 80° C.; and

heating at least the portion of the subject's body to the phase-changetemperature of the phase-change material includes heating at least theportion of the subject's body to a temperature of between 60° C. and 80°C.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, each of the nanoparticles including a plurality of polymerchains disposed between the inner core and the outer layer, the outerlayer being bound to the inner core via the polymer chains.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the polymer chains of each of the nanoparticles includingchains of a polyetheramine.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, each of the nanoparticles including a plurality of polymerchains disposed around its outer layer.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the polymer chains of each of the nanoparticles includingchains of a polyetheramine.

For some applications, administering the plurality of nanoparticles tothe subject includes at least partially masking at least the outer layerof the nanoparticles from phagocytic cells of a mononuclear phagocytesystem of the subject, due to the polymer chains disposed around theouter layer of each of the nanoparticles.

For some applications, heating the portion of the subject's bodyincludes heating the portion of the subject's body by directinginductive radiofrequency heating toward the nano-spheres.

For some applications, directing inductive the radiofrequency heatingtoward the nano-spheres includes transmitting RF energy at a givenfrequency, the nano-spheres having a resonant frequency that matches thegiven frequency.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, each of the nano-spheres of each of the nanoparticles having adiameter that is between 1 nm and 10 nm.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, each of the nano-spheres of each of the nanoparticles having adiameter that is between 3 nm and 7 nm.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, each of the nano-spheres of each of the nanoparticles beingseparated from all others of the nano-spheres of the outer layer of thenanoparticle by a minimum separation of between 0.3 nm and 2 nm.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, each of the nano-spheres of each of the nanoparticles beingseparated from all others of the nano-spheres of the outer layer of thenanoparticle by a minimum separation of between 0.5 nm and 1.5 nm.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the inner core of each of the nanoparticles having a volume of50,000-270,000 nm³.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the inner core of each of the nanoparticles having a volume of85,000-145,000 nm³.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, each of the nanoparticles having a volume of 110,000-700,000nm³.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, each of the nanoparticles having a volume of 180,000-525,000nm³.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the phase-change material of the inner core of thenanoparticles including an organic phase-change material.

For some applications, administering the plurality of nanoparticles tothe subject includes administering the plurality of nanoparticles to thesubject, the phase-change material of the inner core of thenanoparticles including paraffin.

There is additionally provided, in accordance with some applications ofthe present invention, a method including:

synthesizing a nanoparticle to have a volume of at least 65,000 nm3, andto be elongatable into an ellipsoid, such that when the nanoparticle ismaximally elongated:

-   -   each of the semi-axes defined by the ellipsoid is greater than 5        nm, and    -   at least two of the semi axes of the ellipsoid are less than 30        nm, the synthesizing being performed by:    -   providing an inner core that includes a phase-change material        that is configured to absorb latent heat of fusion, by        undergoing a phase change selected from the group consisting of:        solid to liquid, and gel to liquid, the phase-change occurring        at a phase-change temperature of between 42° C. and 80° C.,    -   binding an outer layer to the inner core, the outer layer        including:        -   a plurality of nano-spheres of at least one metal, and        -   a plurality of molecules of a substance that binds            preferentially with cancerous cells relative to            non-cancerous cells.

For some applications, providing the inner core includes providing theinner core, the phase-change material of the inner core having aphase-change temperature of between 42° C. and 50° C.

For some applications, providing the inner core includes providing theinner core, the phase-change material of the inner core having aphase-change temperature of between 50° C. and 60° C.

For some applications, providing the inner core includes providing theinner core, the phase-change material of the inner core having aphase-change temperature of between 60° C. and 80° C.

For some applications, synthesizing the nanoparticle includessynthesizing the nanoparticle to be elongatable in response tohydrostatic pressure.

For some applications, synthesizing the nanoparticle includessynthesizing the nanoparticle to be elongatable in response to osmoticpressure.

For some applications, synthesizing the nanoparticle includessynthesizing the nanoparticle to be elongatable into an ellipsoid, suchthat when the nanoparticle is maximally elongated each of the semi-axesdefined by the ellipsoid is greater than 10 nm.

For some applications, synthesizing the nanoparticle includessynthesizing the nanoparticle to be elongatable into an ellipsoid, suchthat when the nanoparticle is maximally elongated at least two of thesemi axes of the ellipsoid are less than 25 nm.

For some applications, binding the outer layer to the inner coreincludes binding an outer layer to the inner core, the outer layerincluding a plurality of gold nano-spheres.

For some applications, binding the outer layer to the inner coreincludes binding the outer layer to the inner core, the substance thatbinds preferentially with cancerous cells relative to non-cancerouscells including glucose.

For some applications, binding the outer layer to the inner coreincludes binding the outer layer to the inner core, the substance thatbinds preferentially with cancerous cells relative to non-cancerouscells including a glucose derivative.

For some applications, binding the outer layer to the inner coreincludes binding the outer layer to the inner core, the substance thatbinds preferentially with cancerous cells relative to non-cancerouscells including a glucose analog.

For some applications, binding the outer layer to the inner coreincludes binding the outer layer to the inner core, the substance thatbinds preferentially with cancerous cells relative to non-cancerouscells including an antibody.

For some applications, binding the outer layer to the inner coreincludes binding the outer layer to the inner core via a plurality ofpolymer chains.

For some applications, binding the outer layer to the inner coreincludes binding the outer layer to the inner core via a plurality ofchains of a polyetheramine.

For some applications, synthesizing the nanoparticle includes binding aplurality of polymer chains to the outer layer, such that the polymerchains are disposed around the outer layer.

For some applications, binding the plurality of polymer chains to theouter layer includes binding a plurality of chains of a polyetheraminepolymer to the outer layer.

For some applications, binding the outer layer to the inner coreincludes binding an outer layer to the inner core, each of thenano-spheres of the outer layer having a diameter that is between 1 nmand 10 nm.

For some applications, binding the outer layer to the inner coreincludes binding an outer layer to the inner core, each of thenano-spheres of the outer layer having a diameter that is between 3 nmand 7 nm.

For some applications, binding the outer layer to the inner coreincludes binding an outer layer to the inner core, each of thenano-spheres of the outer layer being separated from all others of thenano-spheres of the outer layer by a minimum separation of between 0.3nm and 2 nm.

For some applications, binding the outer layer to the inner coreincludes binding an outer layer to the inner core, each of thenano-spheres of the outer layer being separated from all others of thenano-spheres of the outer layer by a minimum separation of between 0.5nm and 1.5 nm.

For some applications, providing the inner core that includes thephase-change material includes providing an inner core having a volumeof 50,000-270,000 nm³.

For some applications, providing the inner core that includes thephase-change material includes providing an inner core having a volumeof 85,000-145,000 nm³.

For some applications, synthesizing the nanoparticle includessynthesizing the nanoparticle to have a volume of 110,000-700,000 nm³.

For some applications, synthesizing the nanoparticle includessynthesizing the nanoparticle to have a volume of a volume of180,000-525,000 nm³.

For some applications, providing the inner core that includes thephase-change material includes providing an inner core that includes anorganic phase-change material.

For some applications, providing the inner core that includes theorganic phase-change material includes providing an inner core thatincludes paraffin.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-B are schematic illustrations of a subject who is sufferingfrom cancer, a plurality of nanoparticles having been administered tothe subject and having become coupled to a tumor that contains cancerouscells, in accordance with some applications of the present invention;

FIG. 2A is a schematic illustration of a cross-section of thenanoparticle, when, as shown for illustrative purposes, the nanoparticleis in a spherical shape, in accordance with some applications of thepresent invention;

FIGS. 2B-C are schematic illustrations of respective cross-sections ofthe nanoparticle, while the nanoparticle is in an elongatedconfiguration, in which the nanoparticle is shaped as an ellipsoid, inaccordance with some applications of the present invention; and

FIG. 3 is a graph showing results of an experiment in whichnanoparticles as described herein were administered to mice, inaccordance with some applications of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS

Reference is now made to FIGS. 1A-B, which are schematic illustrationsof a subject 20 who is suffering from cancer, a plurality ofnanoparticles 22 having been administered to the subject and havingamassed at a tumor 24 that contains cancerous cells, in accordance withsome applications of the present invention. As shown in FIG. 1B, aheating device 26 is typically used in conjunction with theadministration of the nanoparticles to the subject. The heating devicetransmits energy (schematically illustrated by arrows 28) toward thesubject's body, causing at least some of the cancerous cells to becomeheated, such that the heated cells become injured or ruptured, leadingto cell death. The heating device acts as an energy transmission unit.

As described in detail hereinbelow, the nanoparticles typically have thefollowing characteristics:

(1) The nanoparticles preferentially bind to cancerous cells relative tohealthy cells.

(2) The nanoparticles preferentially absorb energy transmitted towardthe subject's body relative to absorption of the energy by tissue of thesubject.

(3) The nanoparticles prevent healthy tissue surrounding the cancerouscells from being heated to a temperature that is greater than a giventemperature.

(4) The nanoparticles are at least partially self-adjusting in shape,the nanoparticles being configured to be elongatable to an ellipsoidshape such as to pass through a gap in an anatomical barrier that has asize that is greater than a minimum threshold size, for example, inresponse to osmotic and/or hydrostatic pressure being exerted on thenanoparticles.

It is noted that typically, the nanoparticles will not become elongatedto a precise geometric ellipsoid shape, but will assume a generallyellipsoidal shape when maximally elongated.

For some applications, the heating device 26 with which thenanoparticles are used is an RF-transmitter, which heats thenanoparticles via inductive radiofrequency heating. FIG. 1B shows thepatient's body inside the heating device. As shown in the example thatis shown in FIG. 1B, heating device (e.g., the RF-transmitter) mayinclude a housing 27 that is shaped like an MRI scanner, such that theentire body of the subject, or an entire potion of the subject's body(e.g., the subject's torso, as shown) is disposed inside the housing. Acoil 29 spirals around inside the housing and transmits energy in thegeneral direction of the subject's body.

Alternatively or additionally, heating device 26 may include respectivetransmission and receiving electrodes (e.g., electrode plates) that aredisposed on opposite sides of the subject's body (e.g., above and belowthe subject's body). For such applications, the heating device istypically configured to generate an electromagnetic field that passesthrough at least a portion of the subject's body, by transmittingelectromagnetic energy from the transmission electrode to the receivingelectrode.

Further alternatively or additionally, heating device 26 is shapeddifferently and/or transmits energy toward the subject's body in a formother than RF energy. For example, the heating device may be housed in aportable housing, and the housing may be sized such that the energy isdirected toward a specific portion of the subject's body. The heatingdevice may transmit sonic or ultrasonic energy, and/or may transmit adifferent range of electromagnetic energy, e.g., optical energy,infrared energy, UV energy, or microwave energy. In accordance with someapplications of the invention, the heating device may use Joule heating,magnetic heating, electromagnetic heating, electrophoretic heating,and/or inductive heating.

Reference is now made to FIG. 2A, which is a schematic illustration of across-section of nanoparticle 22, in accordance with some applicationsof the present invention. FIG. 2A shows a cross-section of thenanoparticle when the nanoparticle is shaped spherically, forillustrative purposes. Reference is also made to FIGS. 2B and 2C, whichare schematic illustration of respective cross-sections of nanoparticle22, when the nanoparticle is elongated and is shaped as an ellipsoid. Itis noted that, for illustrative purposes, the relative dimensions of therespective components of the nanoparticle are not shown to scale inFIGS. 2A-C.

As shown, nanoparticle 22 typically includes an inner core 30 that is aphase-change material. An outer layer 32 is disposed around the innercore, the outer layer including a plurality of nano-spheres 34 of atleast one metal. It is noted that the outer layer is typically not acontinuous layer, but rather there are separations between each of thenano-spheres and the nano-spheres that are adjacent thereto, asdescribed in further detail hereinbelow. For some applications, polymerchains 36 that define respective hydrophobic and hydrophilic ends aredisposed between inner core 30 and outer layer 32, such that thehydrophobic core is bonded to the phase-change material within the innercore, and the hydrophilic ends are bonded to the nano-spheres of thefirst outer layer. For some applications, polymer chains 37 are disposedaround the outside of outer layer 32, as shown.

As shown in the enlarged portion of FIG. 2A, typically, molecules 38 ofa substance that binds preferentially with cancerous cells relative tonon-cancerous cells are bound to nano-spheres 34. Typically, glucosemolecules, and/or molecules of a glucose analog or a glucose derivative(such as fluorodeoxyglucose and/or D-glucose), are used as the substancethat binds preferentially with cancerous cells relative to non-cancerouscells. Typically, more than twenty times as many glucose (or glucoseanalog or glucose derivative) molecules may become coupled to the cancercells as become coupled to the healthy cells. The preferential uptake ofglucose molecules by cancer cells is based on the Warburg effect,described hereinabove in the Background, and as described in “Cancer'sMolecular Sweet Tooth and the Warburg Effect,” by Kim et al., Cancer Res2006; 66: (18), Sep. 15, 2006, which is incorporated herein byreference. (The principle of cancer cells preferentially uptakingglucose molecules forms the basis of certain PET-CT imaging protocols.)For some applications, glucose (or a glucose analog or a glucosederivative) is used since glucose is absorbed even into anaerobictissue, and cancerous tissue is typically anaerobic. Further typically,glucose, glucose analogs, and glucose derivatives bind with both solidtumors and hematological tumors. For some applications, a different typeof molecule (e.g., an antibody, a drug, and/or a hormone) thatpreferentially binds with cancerous cells relative to non-cancerouscells is used.

For some applications, the nanoparticles are administered to the subjectsystemically (e.g., orally, and/or via intravenous injection), and thenanoparticles are configured to preferentially bind with the cancercells, by virtue of the fact that the nanoparticle includes thesubstance that binds preferentially with cancerous cells relative tonon-cancerous cells. In this manner the nanoparticles typically amass inthe vicinity of a cancerous tumor (e.g., tumor 24, shown in FIG. 1A),and bind with cells of the tumor. For some applications, even in theevent that the cancer has metastasized the nanoparticles amass aroundand bind with metastasized cancer cells.

Typically, outer layer 32 includes a plurality of nano-spheres 34 of atleast one metal. Typically, nano-spheres 34 include a noble metal suchas ruthenium, rhodium, palladium, silver, osmium, iridium, platinum,and/or gold. For some applications, nano-sphere 34 is a paramagneticgold superatom nano-sphere. For some applications, an alloy thatincludes a mixture of two or more metals, or a metal and a nonmetal, isused for nano-spheres 34.

As noted hereinabove, outer layer 32 is typically not a continuouslayer, but rather there are separations between each of the nano-spheresand the nano-spheres that are adjacent thereto. Typically, a diameter ofeach of the nano-spheres is greater than 1 nm (e.g., greater than 3 nm),and/or less than 10 nm (e.g., less than 7 nm), e.g., between 1 and 10nm, or between 3 nm and 7 nm. Further typically, when nanoparticle 22 isin its spherical configuration (FIG. 2A), a separation S between each ofthe nano-spheres and an adjacent nano-sphere is greater than 0.3 nm(e.g., greater than 0.5 nm), and/or less than 2 nm (e.g., less than 1.5nm), e.g., between 0.3 nm and 2 nm, or between 0.5 nm and 1.5 nm. Theseparation between the nano-spheres allows the nano-spheres to move withrespect to each other, which contributes to the nanoparticle having theproperty of being self-adjusting in shape. By contrast, if outer layer32 were to be formed as a continuous layer of metal, the outer layerwould be relatively rigid. The separation between the nano-spheres istypically not greater than the maximum separation described herein, inorder to prevent phagocytic cells of the subject's mononuclear phagocytesystem (i.e., the subject's reticuloendothelial system) from penetratingouter layer 32 and breaking down polymer chains 36 and/or thephase-change material of inner core 30.

As described hereinabove, heating device 26 is typically used totransmit energy (e.g., RF energy) toward the subject's body. Forexample, the heating device may direct inductive radiofrequency heatingtoward the subject's body (and, therefore, toward the nano-spheres). Forsome applications, the heating device directs energy toward thesubject's body at a resonant frequency of nano-spheres 34, and/or afrequency at which the nano-spheres have high energy absorbance relativeto that of the subject's tissue, such that the nano-spherespreferentially absorb energy from the heating device relative to thesubject's tissue (e.g., healthy tissue of the subject). The absorptionof energy by the nano-spheres is such as to heat the nano-spheres. Sincenanoparticles 22 typically amass in the vicinity of cancer cells andbind with the cancer cells, and the nano-spheres preferentially absorbthe energy that is transmitted toward the subject, the cancer cells arepreferentially heated relative to healthy cells of the subject.

Due to the nanoparticles 22 amassing in the vicinity of cancer cells andbinding with the cancer cells, the average heat flux density (i.e., theheat rate per unit area) at the cancer cells within the region of thesubject's body that is heated by the heating device is typicallysubstantially greater (e.g., more than twice as great, more than 5 timesgreater, more than 10 times greater, and/or more than 20 times greater)than that of the average heat flux density at the healthy cells withinthe region that is heated by the heating device. As a result, theheating of the subject's body (or the portion thereof) by the heatingdevice is typically such as to damage the cancer cells in the subject'sbody (or in the heated portion) but not to substantially damage thehealthy cells therein.

Nanoparticle 22 typically includes inner core 30, which includes aphase-change material. Typically, upon being heated to a phase-changetemperature of the phase-change material, the phase-change material isconfigured to undergo a change of phase from solid to liquid, solid togel, or gel to liquid. For some applications, the heating device isconfigured to transmit energy toward the subject's body, such thatnanoparticles 22 are heated to the phase-change temperature of thephase-change material. Typically, due to heat being absorbed by thephase-change material as latent heat of fusion, the temperature of thenanoparticles and in the vicinity of the nanoparticles remainssubstantially constant once the phase-change material has been heated tothe phase-change temperature. Further typically, due to heat beingabsorbed by the phase-change material as latent heat of fusion, theheating device does not heat the cluster to a temperature that isgreater than the phase-change temperature.

Typically, the heating device is configured to heat the nanoparticles tothe phase change temperature of the nanoparticles, but to preventheating of the nanoparticles above the phase-change temperature of thenanoparticles, by effecting a phase change of the nanoparticles. Forsome applications, energy is directed toward the subject's body (or aportion thereof) by the heating device for a period of time that is suchthat the phase-change material absorbs heat without all of the moleculesof the phase change material within inner core 30 changing phase. Inthis manner, heat continues to be absorbed as latent heat of fusion bythe phase-change material within the inner core, throughout the durationof the energy transmission. For example, the heating device may sense atemperature of the clusters using known techniques, and discontinue thetransmission of the energy in response to the sensed temperature (e.g.,in response to the sensed temperature exceeding the phase-changetemperature, which would indicate that heat is no longer being absorbedas latent heat of fusion). Alternatively or additionally, the heatingdevice discontinues transmission of the energy in response to a durationof transmission of the energy, i.e., the unit ceases to transmit energyafter a given time period.

For some applications, during treatment of the subject, the heatingdevice transmits energy in an intermittent manner, the unit alternatingbetween ON periods during which energy is transmitted by the unit, andOFF periods during which energy is not transmitted by the unit, or areduced amount of energy is transmitted by the unit relative to duringthe ON periods. For some applications, the heating device is configuredsuch that the relative durations of the ON and OFF periods of the unitare such as to heat the nanoparticles to the phase change temperature ofthe nanoparticles, but to prevent heating of the nanoparticles above thephase-change temperature of the nanoparticles, in the manner describedhereinabove.

Typically, the phase-change material is chosen such that thephase-change temperature is a temperature at which the cancer cells willbe substantially damaged (e.g., injured or ruptured) but such that thehealthy cells in the surrounding tissue will not be substantiallydamaged. (It is noted that typically some healthy cells may be at leastpartially damaged.) Since the phase-change material maintains thetemperature of the nanoparticles at the phase-change temperature, theheating of the nanoparticles is such as to damage the cancer cells inthe vicinity of the nanoparticles but not to substantially damage thehealthy cells in the vicinity.

For some applications, the effect of the heating of the nanoparticles onthe cancer is in accordance with Table 1, which appears in an article byThomsen, entitled “Pathologic analysis of photothermal andphotomechanical effects of laser-tissue interactions” (PhotochemPhotobiol. 1991 June; 53(6):825-35), which is incorporated herein byreference:

TABLE 1 Histopathological effect of heating on cells Temperature Thermalof onset: damage range Heating Histopathology mechanism (° C.) timeseffect Low-temperature 40-45 Hours Reversible cell damage injury: heataccumulation inactivation of processes enzymes; metabolic accelerationLow 40+ Hours to Edema and minutes hyperemia  43-45+ Hours Cell death:deactivation of enzymes Unknown Unknown Cell shrinkage andhyperchromasia  43+ Minutes Birefringence loss in frozen and thawedmyocardium  45+ Minutes to Thermal seconds denaturization of structuralproteins in fresh tissue Unknown Unknown Cell membrane rupture 50-90Minutes to Hyalinization seconds of collagen 54-78 3.6 to 0.4Birefringence seconds loss in laser irradiated fresh myocardium  55-95+Minutes Birefringence changes in collagen Water 100± SecondsExtracellular dominated vacuole processes formation. Rupture of“popcorn” vacuoles, effect 100-200 Seconds to Tissue millisecondsablation by explosive fragmentation Over 200 Seconds to Tissuepicoseconds ablation

Typically, as stated hereinabove, the region of the subject's body inwhich cancer cells are located is heated to the phase-change temperatureof the phase-change material. For some applications, a phase-changematerial having a phase-change temperature of more than 42° C. and/orless than 80° C. (e.g., 42-80° C.) is used. For example, thephase-change material may have a phase-change temperature of more than42° C. and/or less than 50° C. (e.g., 42-50° C.), more than 50° C.and/or less than 60° C. (e.g., 50-60° C.), or more than 60° C., and/orless than 80° C. (e.g., 60-80° C.).

For some applications, one or more of the phase-change materials thatappear in Table 2 and/or in Table 3 (which are extracted from Zalba etal., Applied Thermal Engineering, 23(3), February 2003, pp. 251-283) isused as the phase-change material of inner core 30.

TABLE 2 Melting temperatures of paraffin particles Melting Heat oftemperature fusion Compound (° C.) (Kj/Kg) Paraffin C16-C28 42-44 189Paraffin C20-C33 48-50 189 Paraffin C22-C45 58-60 189 Paraffin wax 64173.6 Paraffin C28-C50 66-68 189 Paraffin RT40 43 181 Paraffin RT50 54195 Paraffin RT65 64 207 Paraffin RT80 79 209 Paraffin RT90 90 197Paraffin RT110 112 213

TABLE 3 Melting temperature of organic phase-change materials: HeatMelting of Temperature Fusion Compound (° C.) (Kj/Kg) Paraffin C14 4.5165 Paraffin C15-C16 8 153 Polyglycol E400 8 99.6 Dimethyl-sulfoxide(DMS) 16.5 85.7 Paraffin C16-C18 20-22 152 Polyglycol E600 22 189Paraffin C13-C24 22-24 189 1-Dodecanol 26 200 Paraffin C18 28 2441-Tetradecanol 26 200 Paraffin C16-C28 42-44 189 Paraffin C20-C33 48-50189 Paraffin C22-C45 58-60 189 Paraffin Wax 64 173.6 Polyglycol E6000 66190 Paraffin C28-C30 66-68 189 Biphenyl 71 119.2 Propionamide 79 168.2Naphthalene 80 147.7 Erythritol 118 339.8 HDPE 100-150 200Trans-1,4-polybutadiene 145 144 (TPB)

For some applications, one or more of the following organic phase-changematerials is used for the phase-change material of inner core 30: crudeoil, paraffin produced by the Fischer-Tropsch process, and an organicmaterial having saturated, unsaturated, straight, or branched carbonchain particles. The phase-change material may include, for example,trilaurin, trimyristin, tripalmitin, tristearin, and/or any suitabletype of paraffin or paraffin wax.

For some applications, an organic phase-change material is used in innercore 30. For example, paraffin and/or fatty acid particles may be used.For some applications, an organic material is used in inner core 30because the organic phase-change material freezes without substantialsuper cooling, is able to melt congruently, has self-nucleatingproperties, does not segregate, is chemically stable, has a high heat offusion, and/or for a different reason. For some applications, one ormore of the following phase-change materials is used in inner core 30:Octadecane (CAS Number 593-45-3), Lauric acid (CAS No: 143-07-7),Myristic acid (CAS No: 544-63-8), Palmitic acid (CAS No: 57-10-3),Heptadecanoic acid (CAS No: 506-12-7), Stearic acid (CAS No: 57-11-4),Arachidic acid (CAS No: 506-30-9), Behenic acid (Cas No: 112-85-6)Trimethylolethane (CAS No:77-85-0), Stearamine (Octadecylamine)(Sigma-74750), Cetylamine (Hexadecylamine) (Sigma-445312).

In accordance with respective applications of the invention, selectioncriteria for selecting the phase-change material for use in inner core30 include thermodynamic, kinetic, and chemical properties of thephase-change material. For some applications, the phase-change materialis selected to have given thermodynamic properties, such as a meltingtemperature in the desired operating temperature range, a high latentheat of fusion per unit volume, high specific heat, high density, highthermal conductivity, small volume changes on phase transformation,small vapor pressure at operating temperatures, and/or congruentmelting. For some applications, the phase-change material is selected tohave given kinetic properties, such as a high nucleation rate, and/or ahigh rate of crystal growth. For some applications, the phase-changematerial is selected to have given chemical properties, such as chemicalstability, reversibility of the phase-change cycle without degradationof the particles after a large number of phase-change cycles,non-corrosiveness, and/or non-toxicity.

For some applications, the phase-change material has relatively lowthermal conductivity, and is arranged to have a large surface area toovercome the low thermal conductivity and increase the flow of heat intothe phase-change material.

As described hereinabove, and as shown in the transition from FIG. 2A toFIG. 2B, typically, nanoparticle 22 is at least partially self-adjustingin shape, the nanoparticles being configured to be elongatable to agenerally ellipsoid shape (e.g., a tri-axial ellipsoid shape, or aprolate or oblate ellipsoid of revolution shape). It is noted thattypically, the nanoparticle will not become elongated to a precisegeometric ellipsoid shape, but will assume a generally ellipsoidal shapewhen maximally elongated.

Typically, in order for a cancer treatment as described herein to beeffective, nanoparticles 22 need to have a certain minimum volume, forat least one of the following reasons:

(1) Tumor cells tend not to bind with particles that are below a givenvolume.

(2) A minimum volume of nano-spheres 34 of metal is required such as tofacilitate preferential absorption of energy by nanoparticles 22. Inthis manner, the average heat flux density at the cancer cells withinthe region of the subject's body that is heated by the heating device issubstantially greater than that of the average heat flux density at thehealthy cells within the region that is heated by the heating device, asdescribed hereinabove.

(3) It is required that the inner core of phase-change material have agiven minimum volume, in order for the phase-change material toeffectively absorb heat as latent heat of fusion, such as to prevent thetemperature of the nanoparticle from rising above the phase-changetemperature.

Typically, inner core 30 of the phase-change material has a volume of atleast 15,000 nm³, e.g., at least 50,000 nm³, or at least 85,000 nm³. Forsome applications, inner core 30 of the phase-change material has avolume of less than 400,000 nm³, e.g., less than 270,000 nm³, or lessthan 145,000 nm³. For example, inner core 30 may have a volume of15,000-400,000 nm³, e.g., 50,000-270,000 nm³, or 85,000-145,000 nm³.

For some applications, when inner core 30 is shaped spherically (asshown, for illustrative purposes, in FIG. 2A), inner core 30 of thephase-change material has a diameter of at least 30 nm, e.g., at least45 nm, or at least 55 nm. For some applications, when inner core 30 isshaped spherically, inner core 30 of the phase-change material has adiameter of less than 90 nm, e.g., less than 80 nm, or less than 65 nm.For example, when inner core 30 is shaped spherically, inner core 30 mayhave a diameter of 30-90 nm, e.g., 45-80 nm, or 55-65 nm.

As described hereinabove, typically, the diameter of each ofnano-spheres 34 is greater than 1 nm (e.g., greater than 3 nm), and/orless than 10 nm (e.g., less than 7 nm), e.g., between 1 and 10 nm, orbetween 3 nm and 7 nm. The length of each of polymer chains 36, when thechain is maximally straightened, is typically greater than 1 nm (e.g.,greater than 1.5 nm), and/or less than 4 nm (e.g. less than 3 nm), e.g.,1-4 nm, or 1.5-3 nm. The length of each of polymer chains 37, when thechain is maximally straightened, is typically greater than 2 nm (e.g.,greater than 4 nm), and/or less than 10 nm (e.g. less than 8 nm), e.g.,2-10 nm, or 4-8 nm.

Nanoparticle 22 typically has a volume of at least 65,000 nm³, e.g., atleast 110,000 nm³, or at least 180,000 nm³. Further typically, in itsspherical configuration, the nanoparticle has a diameter of less than900,000 nm³, e.g., less than 700,000 nm³, or less than 525,000 nm³. Forsome applications, the nanoparticle has a volume of 65,000-900,000 nm³,e.g., 110,000-700,000 nm³, or 180,000-525,000 nm³.

When it is shaped spherically (as shown, for illustrative purposes, inFIG. 2A), nanoparticle 22 typically has a diameter of at least 50 nm,e.g., at least 60 nm, or at least 70 nm. Further typically, in itsspherical shape, the nanoparticle has a diameter of less than 120 nm,e.g., less than 110 nm, or less than 100 nm. For some applications, inits spherical shape, the nanoparticle has a diameter of 50-120 nm, e.g.,60-110 nm, or 70-100 nm. (It is noted that, although the term“nanoparticle” is typically defined as a particle between 1 and 100nanometers in size, the scope of the present application includes ananoparticle 22 having a size that is slightly greater than 100 nm,e.g., up to 120 nm, as described.)

It is noted that, solely for illustrative purposes, nanoparticle 22 isshown in FIG. 2A in a spherical configuration, and the dimensions ofnanoparticle 22 are provided hereinabove, for when the nanoparticle isshaped spherically. However, nanoparticle 22 does not necessarily assumea spherical shape when in the subject's blood stream, even if thenanoparticle is not being subjected to osmotic, hydrostatic, and/or anyother pressure inside the body. Rather, the nanoparticle may assume, forexample, a tear shape, a bobble shape, an ellipsoid shape, and/or may beamorphous. However, nanoparticle 22 does have a substantially fixedvolume, as provided hereinabove. Furthermore, the nanoparticle istypically configured to be at least partially self-adjusting in shape,such that the nanoparticle is able to pass through an anatomical barrierhaving a size that is greater than a threshold minimum size, forexample, in response to hydrostatic and/or osmotic pressure beingexerted on the nanoparticle, as described in further detail hereinbelow.

Typically, the following features of nanoparticle 22 contribute to thenanoparticle being self-adjusting in shape:

1) Inner core 30 is made of a phase change material, such as paraffin,which is amorphous.

2) Nano-spheres 34 are disposed at the end of polymer chains 36 at aseparation from one another, such that each of the nano-spheres is ableto move with respect to the other nano-spheres.

3) Polymer chains 36 and polymer chains 37 are deformable and may changeshape, for example, from a straight line to a coiled configuration.

Typically, nanoparticles 22 are administered to the subject systemically(e.g., orally, and/or intravenously). For some applications, in order toprevent the liver, spleen, glands, and/or any portion of the subject'smononuclear phagocyte system (i.e., the subject's reticuloendothelialsystem), from filtering the nanoparticles out of the subject's blood,the nanoparticles are configured to elongate (as shown schematically inFIGS. 2B and 2C) into a generally ellipsoid shape, such that at leasttwo of the semi-axes of the ellipsoid have a diameter of less than 30nm, e.g., less than 25 nm. For example, as shown in FIG. 2C, one of thesemi axes of the nanoparticle SA1 is typically less than 30 nm, e.g.,less than 25 nm, and a second one of the semi axes of the nanoparticleSA2 is typically less than 30 nm, e.g., less than 25 nm.

For some applications, even in its maximally elongated configuration(i.e., in the configuration in which the nanoparticle is elongated intoa generally ellipsoidal shape, but cannot be any further elongated),nanoparticle 22 is configured such that each of the semi axes of theellipsoid is greater than 5 nm, e.g., greater than 10 nm. For example,as shown in FIG. 2C, both semi axes SA1 and SA2 are greater than 5 nm,e.g., greater than 10 nm. For some applications, in this manner, thenanoparticle is prevented from traversing the blood brain barrier. Asdescribed hereinabove, outer layer 32 includes molecules of a substancethat binds preferentially with cancerous cells relative to non-cancerouscells. Some of the substances that preferentially bind with cancer cells(e.g., antibodies, glucose, and glucose analogs or derivatives (such asfluorodeoxyglucose and/or D-glucose)) also have preferential uptake bythe brain relative to the rest of the body. Therefore, nanoparticle 22is typically configured such that even in its maximally elongatedconfiguration, each of the semi axes of the ellipsoid is greater than 5nm, e.g., greater than 10 nm, in order to prevent the nanoparticle frombeing able to traverse the blood brain barrier.

As described hereinabove, typically, polymer chains 36 define respectivehydrophobic and hydrophilic ends, and are disposed between inner core 30and outer layer 32. Typically, a polyetheramine, e.g., a Jeffamine®polyetheramine, such as polyethylene glycol (PEG) or polypropylene, isused in polymer chains 36. Typically, polymer chains 36 act to bind theinner core 30 to outer layer 32, and contribute to the self-adjustingproperty of nanoparticle 22 as described herein. Further typically,typically, polymer chains 37 are disposed around outer layer 32.Typically, a polyetheramine, e.g., a Jeffamine® polyetheramine, such aspolyethylene glycol (PEG) or polypropylene, is used in polymer chains37. Polymer chains 37 at least partially mask other components ofnanoparticle 22 (e.g., outer layer 32) from phagocytic cells of thesubject's mononuclear phagocyte system (i.e., the subject'sreticuloendothelial system), thereby preventing the nanoparticle frombeing broken down by the phagocytic cells.

For some applications, the methods described herein are applied to thesubject while imaging the subject, for example, using CT, sonic,ultrasonic, and/or MRI imaging protocols. For some applications, thesubstance is administered to the subject, and the subject's body (or aregion thereof) is irradiated with the energy that is preferentiallyabsorbed by the clusters, as described herein. While the subject's bodyis irradiated, the subject's body is imaged using a heat-sensitiveimaging protocol (for example, using MRI) to detect which regions of thesubject's body (including cancer cells) have been heated.

Experimental Data

Nanoparticles including paraffin engulfed with PPO-PEO-PPO/PEO (asgenerally described hereinabove) were prepared by using anemulsification/solvent evaporation method. Drops of a solution ofparaffin wax in dichloromethane were added into an aqueous solution ofN,N-Methyl Bisacrylamide (BIS) and a mixture of an acrylated tri/diblockcopolymer. Jeffamine® 1900 was used as the tri/diblock copolymer.Jeffamine® 1900 is a block copolymer composed ofpolypropylene-oxide/polyethylene-oxide: NH2-PPO-PEO-PPO-NH2,functionalized with polymerizable acrylamide groups either (a) at oneend, such as to provide a positively charged di-block copolymer of typeacryl-NH-A-B-NH3+, or (b) at both ends, such as to provide a tri-blockco-polymer of type acryl-NH-B-A-B-NH-acryl.

The mixture was subjected to ultrasonication to form a stableoil-in-water emulsion. Once residual solvent within the droplets wasevaporated, nanoparticles of PPO-PEO-PPO/PEO engulfing paraffin wax wereobtained, in a nano-reservoir structure. Since the monomers possesspolymerizable functions, radical activation at elevated temperature wasused to start polymerization and cross-linking within the self-assembledparticles, resulting in the formation of nanoparticles with aPEO-PPO-PEO/PEO cross-linked shell structure with an oil-filled core inthe interior. The resultant nanoparticles possessed terminal aminegroups which acted as attachment points for small colloidal goldparticles. The attachment points were used as nucleation sites for thecoalescence of a thin gold overlayer usingtetrakis(hydroxymethyl)phosphonium chloride (THPC) as a reducing agent.As described hereinabove, the gold nano-spheres were bonded to thenanoparticles, such that each of the gold nano-spheres was separatedfrom all of the other nano-spheres in the overlayer, such that theoverlayer formed a segmented shell. The segmented shell thickness wascontrolled using chloroauric acid and ammonium hydroxide.

SH-PEG2K-Fluorescein isothiocyanate (FITC) was added to1-Thio-β-D-glucose sodium salt and the mixed solution was added to theencapsulated paraffin nanoparticles. The mixture was vortexed for 10 minand then shaken in an orbital shaker at room temperature for 24 h. Thenanoparticles were then centrifuged before being re-dispersed andwashed.

Having prepared the nanoparticles in the above-described manner, thenanoparticles were used to perform an experiment on a set of mice. Tumorcells were injected subcutaneously into the set of mice. The volumes ofthe subcutaneous tumors were measured daily. When the tumor of a givenmouse reached 300 mm³ in volume, the mouse was injected with thenanoparticles. The mice were weighed, and a volume of 10 micro-liters ofthe nanoparticles were injected, per gram of weight of the mouse. Afteradministering the nanoparticles to the mice, the mice were sacrificed atrespective times subsequent to the administration of the nanoparticlesto the respective mice. Organs, such as the liver and the spleen, ofeach of the mice were harvested, as was the tumor of each of the mice.The organs, as well as the tumor were weighed, and subsequently, theorgans and the tumor were placed in acid, such that all of the organicmatter dissolved. The matter that remained from each of the organs andthe tumor was then analyzed using inductively coupled plasma massspectrometry (ICP-MS), in order to detect the amount of gold (from thegold nano-spheres of the nanoparticles) that was present in each of theorgans and the tumor. In this manner, the amount of gold per unit weightof tissue was determined for the liver and the spleen, and the tumor.Since, even after being placed in the acid, the gold from thenanoparticles remains intact, the amount of gold present in the organsand tumors of the mice is indicative of the volume of nanoparticles thatreached the organs and the tumor.

FIG. 3 is a graph showing the results of the above-described experiment.The dashed curve shows a plot of the amount of gold (in micrograms ofgold, per milligram of tissue) that was present in the livers and thespleens of mice that were sacrificed at respective time periods afteradministration of the nanoparticles to the mice. The solid line shows aplot of the amount of gold that was present in the tumors of the micethat were sacrificed at the respective time periods after theadministration of the nanoparticles to the mice. The graph is based ondata from mice that were sacrificed, respectively, 15 minutes, 30minutes, 60 minutes, 120 minutes, and 240 minutes after theadministration of the nanoparticles to the mice.

As stated hereinabove, the amount of gold that was present in the organsand tumors of the mice is representative of the volume of nanoparticlesthat reached the organs and the tumor. It may be observed that, overtime, the amount of gold that is present in the liver and spleendecreases, while the amount of gold that is present in the tumorincreases. These results indicate that nanoparticles as described herein(a) are capable of passing through the liver and spleen due the factthat the nanoparticles are self-adjusting in shape, and (b) accumulatein the vicinity of cancerous cells, due to the tendency of thenanoparticles to preferentially bind to cancerous cells.

For some applications, the apparatus and methods described herein areperformed in combination with apparatus and methods described in US2012/0221081 to Hof, which is incorporated herein by reference.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

1. Apparatus for use with a subject suffering from cancer, a body of thesubject containing cancerous cells and non-cancerous cells, and for usewith a heating device configured to heat at least a portion of thesubject's body, the apparatus comprising: a nanoparticle comprising: aninner core that comprises a phase-change material that is configured toabsorb latent heat of fusion by undergoing a phase change selected fromthe group consisting of: solid to liquid, and gel to liquid, thephase-change occurring at a phase-change temperature of between 42° C.and 80° C.; an outer layer disposed around the inner core, the outerlayer comprising: a plurality of nano-spheres of at least one metal; anda plurality of molecules of a substance that binds preferentially withcancerous cells relative to non-cancerous cells, the nanoparticle havinga volume of at least 65,000 nm³, the nanoparticle being elongatable intoan ellipsoid, such that when the nanoparticle is maximally elongated:each of the semi-axes defined by the ellipsoid is greater than 5 nm, andat least two of the semi axes of the ellipsoid are less than 30 nm. 2-4.(canceled)
 5. The apparatus according to claim 1, wherein thenanoparticle is configured to become elongated in response tohydrostatic pressure within the subject's body.
 6. The apparatusaccording to claim 1, wherein the nanoparticle is configured to becomeelongated in response to osmotic pressure within the subject's body. 7.The apparatus according to claim 1, wherein the nanoparticle isconfigured to be blocked from passing through a blood brain barrier ofthe subject, by being elongatable into an ellipsoid, such that even whenthe nanoparticle is maximally elongated, each of the semi-axes definedby the ellipsoid is greater than 5 nm.
 8. The apparatus according toclaim 1, wherein the nanoparticle is configured to be able to passthrough a liver of the subject, by being elongatable into an ellipsoid,such that when the nanoparticle is maximally elongated at least two ofthe semi axes of the ellipsoid are less than 30 nm.
 9. The apparatusaccording to claim 1, wherein the nanoparticle is configured to be ableto pass through glands of the subject, by being elongatable into anellipsoid, such that when the nanoparticle is maximally elongated atleast two of the semi axes of the ellipsoid are less than 30 nm.
 10. Theapparatus according to claim 1, wherein the nanoparticle is configuredto be able to pass through a mononuclear phagocyte system of thesubject, by being elongatable into an ellipsoid, such that when thenanoparticle is maximally elongated at least two of the semi axes of theellipsoid are less than 30 nm.
 11. The apparatus according to claim 1,wherein the nanoparticle is configured to be able to pass through aspleen of the subject, by being elongatable into an ellipsoid, such thatwhen the nanoparticle is maximally elongated at least two of the semiaxes of the ellipsoid are less than 30 nm.
 12. The apparatus accordingto claim 1, wherein the phase-change material is configured to preventthe nanoparticle from being heated to a temperature that is greater thanthe phase change temperature, by absorbing latent heat of fusion. 13-14.(canceled)
 15. The apparatus according to claim 1, wherein thenano-spheres of the at least one metal are configured to cause thenanoparticle to preferentially absorb energy from the heating devicerelative to tissue of the subject.
 16. The apparatus according to claim1, wherein the nano-spheres of the at least one metal comprise goldnano-spheres. 17-20. (canceled)
 21. The apparatus according to claim 1,wherein the nanoparticle further comprises a plurality of polymer chainsdisposed between the inner core and the outer layer, the outer layerbeing bound to the inner core via the polymer chains.
 22. (canceled) 23.The apparatus according to claim 1, wherein the nanoparticle furthercomprises a plurality of polymer chains disposed around the outer layer.24. (canceled)
 25. The apparatus according to claim 23, wherein thepolymer chains are configured to at least partially mask at least theouter layer from phagocytic cells of a mononuclear phagocyte system ofthe subject.
 26. The apparatus according to claim 1, wherein thenanoparticles are configured to be used with an inductive radiofrequencyheating device, and wherein the nano-spheres are configured to be heatedby the inductive radiofrequency heating device.
 27. The apparatusaccording to claim 26, wherein the nanoparticles are configured to beused with an inductive radiofrequency heating device that transmits RFenergy at a given frequency, and wherein the nano-spheres have aresonant frequency that matches the given frequency.
 28. The apparatusaccording to claim 1, wherein each of the nano-spheres has a diameterthat is between 1 nm and 10 nm.
 29. (canceled)
 30. The apparatusaccording to claim 1, wherein each of the nano-spheres is separated fromall others of the nano-spheres of the outer layer by a minimumseparation of between 0.3 nm and 2 nm.
 31. (canceled)
 32. The apparatusaccording to claim 1, wherein the inner core has a volume of50,000-270,000 nm³. 33-35. (canceled)
 36. The apparatus according toclaim 1, wherein the phase-change material comprises an organicphase-change material. 37-75. (canceled)
 76. A method comprising:synthesizing a nanoparticle to have a volume of at least 65,000 nm3, andto be elongatable into an ellipsoid, such that when the nanoparticle ismaximally elongated: each of the semi-axes defined by the ellipsoid isgreater than 5 nm, and at least two of the semi axes of the ellipsoidare less than 30 nm, the synthesizing being performed by: providing aninner core that includes a phase-change material that is configured toabsorb latent heat of fusion, by undergoing a phase change selected fromthe group consisting of: solid to liquid, and gel to liquid, thephase-change occurring at a phase-change temperature of between 42° C.and 80° C., binding an outer layer to the inner core, the outer layerincluding: a plurality of nano-spheres of at least one metal, and aplurality of molecules of a substance that binds preferentially withcancerous cells relative to non-cancerous cells. 77-79. (canceled) 80.The method according to claim 76, wherein synthesizing the nanoparticlecomprises synthesizing the nanoparticle to be elongatable in response tohydrostatic pressure.
 81. The method according to claim 76, whereinsynthesizing the nanoparticle comprises synthesizing the nanoparticle tobe elongatable in response to osmotic pressure. 82-83. (canceled) 84.The method according to claim 76, wherein binding the outer layer to theinner core comprises binding an outer layer to the inner core, the outerlayer including a plurality of gold nano-spheres. 85-88. (canceled) 89.The method according to claim 76, wherein binding the outer layer to theinner core comprises binding the outer layer to the inner core via aplurality of polymer chains.
 90. (canceled)
 91. The method according toclaim 76, wherein synthesizing the nanoparticle comprises binding aplurality of polymer chains to the outer layer, such that the polymerchains are disposed around the outer layer.
 92. (canceled)
 93. Themethod according to claim 76, wherein binding the outer layer to theinner core comprises binding an outer layer to the inner core, each ofthe nano-spheres of the outer layer having a diameter that is between 1nm and 10 nm.
 94. (canceled)
 95. The method according to claim 76,wherein binding the outer layer to the inner core comprises binding anouter layer to the inner core, each of the nano-spheres of the outerlayer being separated from all others of the nano-spheres of the outerlayer by a minimum separation of between 0.3 nm and 2 nm.
 96. (canceled)97. The method according to claim 76, wherein providing the inner corethat includes the phase-change material comprises providing an innercore having a volume of 50,000-270,000 nm³. 98-100. (canceled)
 101. Themethod according to claim 76, wherein providing the inner core thatincludes the phase-change material comprises providing an inner corethat includes an organic phase-change material.
 102. (canceled)